Public Release: 

Enzyme discovery sheds light on causes of rare disease, cancer

NIH/National Institute on Aging

Discovery of a new enzyme, PHF9, is providing insight into the biological processes involved in development of Fanconi anemia (FA), a rare genetic disorder that primarily affects children. The detection of the enzyme enhances understanding of the common DNA repair pathways involved in FA, as well as certain cancers and aging, scientists say. Better understanding of these pathways could lead to new therapies for Fanconi anemia.

Scientists at the National Institute on Aging (NIA) found that genetic mutations in an important protein complex inactivate PHF9. This disrupts critical intracellular repair mechanisms and leads to many serious complications associated with FA including the inability to make red blood cells.

"FA is a disease that appears to be the result of breakdowns in DNA repair mechanisms, which are important for all of us," said Weidong Wang, Ph.D., an investigator in the NIA's Laboratory of Genetics. "Some scientists theorize that DNA damage, which gradually accumulates as we age, leads to malfunctioning genes and deteriorating tissues and organs as well as increased risks of cancer as years go by. So every time we learn something more about DNA repair, we can hope to use that new knowledge to find ways to prevent the excessive damage to DNA that appears to occur with aging."

The finding is scheduled for advanced online publication in the journal, Nature Genetics (, during the week of September 14, 2003. The report also will be published in journal's October 2003 print edition.

Dr. Wang and his colleagues detected PHF9 and its corresponding gene while attempting to verify the existence of the Fanconi protein complex and identify its structure. Based on earlier work, the researchers suspected that the complex incorporated proteins produced by at least five previously known FA genes. Today's findings not only confirm that the complex exists, they also for the first time describe its composition, which includes nearly all of the proteins produced by the previously known FA genes plus PHF9 and several other new proteins.

The FA complex normally promotes a cascade of changes in a biochemical pathway that ultimately leads to the repair of cellular DNA damage. But if any of the proteins within the complex--including PHF9 itself--are mutated, the enzyme is disabled and the DNA repair pathway is disrupted. As a result, the person develops FA. Other researchers have found that similar disruptions in this DNA repair pathway can contribute to the development of ovarian, pancreatic, and other cancers in people who aren't at risk for FA. This suggests that PHF9 is a potent cog within the DNA repair machinery, Dr.Wang said.

"What makes the discovery of PHF9 particularly important is that none of the previously known FA gene products are enzymes," Dr.Wang said. "So the PHF9 enzyme is the key. All of the other proteins in this complex function through it. If you think of the FA complex as a factory, PHF9 is the machine that creates the product. Without it, the complex makes nothing."

Fanconi anemia, named for Swiss pediatrician, Guido Fanconi, affects about 1 in every 300,000 children. If both parents have the same mutation in the same FA gene, each of their children has a one-in-four chance of inheriting the defective gene from both parents and developing FA or certain types of cancer.

The disease leads to bone marrow failure (aplastic anemia) and is associated with birth defects such as missing or extra thumbs and skeletal abnormalities of the hips, spine or ribs. Many who have FA eventually develop acute myelogenous leukemia and are prone to head and neck, gastrointestinal and other cancers. The first symptoms, such as nose bleeds or easy bruising, usually begin before age 12. In rare instances, however, symptoms do not become apparent until adulthood.

The Nature Genetics report represents a hopeful new area of scientific inquiry for those who have the disease and their families, said David Frohnmayer, president of the University of Oregon in Eugene and a spokesman for the Fanconi Anemia Research Fund, He and his wife, Lynn, helped incorporate the Fund in 1989. Two of their daughters have died of complications from the disease.

"Anything that can be found to further explain the FA complex and its functions is extremely important not only for the people who suffer from this disorder, but for the world of scientific discovery at the molecular level generally and especially those interested in DNA repair and cancer," Frohnmayer said. "This is the kind of discovery that takes a rare orphan disease and puts it in the mainstream of important science that affects the lives of millions of people."

In addition to NIA, researchers at the Baylor College of Medicine in Houston, the Oregon Health & Science University in Portland, and the Free University Medical Center in Amsterdam, The Netherlands, contributed to this work.


The NIA is one of 27 Institutes and Centers of the National Institutes of Health in the U.S. Department of Health and Human Services. The NIA leads Federal efforts to support and conduct basic, clinical, epidemiological, and social research on aging and the special needs of older people. Press releases, fact sheets, and other materials about aging and aging research can be viewed at the NIA's general information web site,

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